WO2007043606A1 - Agent antidiabétique comprenant un complexe métal-polyamino acide anionique - Google Patents

Agent antidiabétique comprenant un complexe métal-polyamino acide anionique Download PDF

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WO2007043606A1
WO2007043606A1 PCT/JP2006/320375 JP2006320375W WO2007043606A1 WO 2007043606 A1 WO2007043606 A1 WO 2007043606A1 JP 2006320375 W JP2006320375 W JP 2006320375W WO 2007043606 A1 WO2007043606 A1 WO 2007043606A1
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Prior art keywords
metal
complex
polyamino acid
vanadium
composition according
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PCT/JP2006/320375
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English (en)
Japanese (ja)
Inventor
Hiromu Sakurai
Yutaka Yoshikawa
Subarna Karmaker
Tapan Kumar Saha
Tomomitsu Sewaki
Yasushi Osanai
Mie Iwamoto
Jae-Chul Choi
Chung Park
Moon-Hee Sung
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Genolac Bl Corporation
Bioleaders Corporation
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Priority to JP2007539976A priority Critical patent/JPWO2007043606A1/ja
Publication of WO2007043606A1 publication Critical patent/WO2007043606A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A23L33/165—Complexes or chelates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a pharmaceutical composition for treating / preventing diabetes, comprising an anionic polyamino acid, preferably a metal polyamino acid complex that can be produced from polygamma glutamic acid and a metal compound. More specifically, the present invention relates to an anionic polyamino acid, preferably poly-gamma-glutamic acid and a metal compound that can be produced, and a metal-polyamino acid complex that can be produced. The present invention relates to a pharmaceutical composition for the prevention of diabetes having at least one of a lowering action and an insulin resistance improving action. The present invention also relates to a complex of an anionic polyamino acid, preferably polygamma-glutamic acid and vanadium.
  • Diabetes mellitus one of lifestyle-related diseases, is listed as one of the three major diseases in the 21st century. It is said that the number of patients diagnosed with diabetes and their reserves will reach 20 million. Yes. Diabetes can be broadly divided into “splenic ⁇ -cells are exhausted due to autoimmune knee nephritis, etc.” Insulin-dependent type 1 diabetes and “because of lifestyle habits such as obesity, overeating, lack of exercise, and irregular lifestyles” It is largely divided into non-insulin-dependent type 2 diabetes. Among these diabetics, treatment of type 1 diabetes can only be painful for patients who have only a few daily insulin injections.
  • vanadium sulfate (IV) is known as a drug having an insulin-like action, and is already used in clinical trials in the United States and the like.
  • vanadium oxide (IV) sulfate is an inorganic salt, vanadium (IV) having various ligands such as cysteine methyl ester as a ligand, which is difficult to be taken into the living body, which is difficult to permeate through biological membranes.
  • Vanadium (IV) having a dihydroxydicarboxylate or hydroxypyranone derivative as a ligand Vanadium (IV) having a dihydroxydicarboxylate or hydroxypyranone derivative as a ligand, ⁇ substituted dithiopower rubamate
  • vanadium (IV) and the like having a ligand as a ligand have been developed, these vanadium (IV) compounds also have a practical stage in terms of action and side effects! /.
  • organic substances such as picolinic acid and maltol
  • poly gamma glutamic acid has the following formula:
  • Polygamma glutamic acid is known as the main substance of stringing of natto and is expected to have various uses in many fields such as food, cosmetics and medical products.
  • Polygamma glutamic acid is mainly produced by culturing microorganisms such as strains of the genus Bacillus.
  • Poly-gamma-glutamic acid is a biodegradable polymer, and the polymer or the polymer cross-linked with radiation or metal (aluminum, chromium, iron, etc.) is used as a material for water-absorbing polymers and coagulants.
  • Patent Documents 4 and 5 It has been used (see Patent Documents 4 and 5). In addition, it has been reported that it is used as a hair cosmetic material (see Patent Document 6) or as an external preparation component for introducing ions into the skin (see Patent Document 7) because of its moisturizing property.
  • Poly-gamma-glutamate is known to promote the absorption of calcium in the small intestine, and this action is due to the carboxyl group of poly-gamma glutamate binding to calcium and making it soluble. Is.
  • poly-gamma-glutamate is different from normal proteins, and since amino acids are linked by ⁇ bonds, human proteases cannot cleave the ⁇ bonds and are not digested in the small intestine. Glutamate acts as a dietary fiber in the small intestine.
  • polygamma glutamic acid has viscosity, nutrients are gradually absorbed by restricting the movement of food in the small intestine, and therefore, it is expected to have an effect of gently easing the sugar concentration by gently absorbing the sugar content.
  • poly-gamma-glutamic acid includes an immunopotentiating action (see Patent Document 12), a mineral absorption promoting action (see Patent Document 13), and a tooth remineralization promoting action (see Patent Document 14).
  • Patent Document 12 an immunopotentiating action
  • Patent Document 13 a mineral absorption promoting action
  • Patent Document 14 a tooth remineralization promoting action
  • Patent Document 1 JP 2000-44584 A
  • Patent Document 2 JP 2000-281650 A
  • Patent Document 3 Japanese Patent Application Laid-Open No. 2001-11083
  • Patent Document 4 JP 2001-181387 A
  • Patent Document 5 JP 2002-210307 A
  • Patent Document 6 Japanese Patent Laid-Open No. 2005-154352
  • Patent Document 7 JP 2005-35957 A
  • Patent Literature 8 Special Table 2003—-527443
  • Patent Document 9 Special Table 2003—-511423
  • Patent Document 10 Special Table 2003-525912
  • Patent Document 11 Japanese Patent Laid-Open No. 2005-200330
  • Patent Document 12 Japanese Unexamined Patent Application Publication No. 2005-187427
  • Patent Document 13 Korean Patent Application No. 10-2003-0046898
  • Patent Document 14 Japanese Unexamined Patent Application Publication No. 2005-255645
  • An object of the present invention is to provide a drug that is safe and has an anti-diabetic action, and that can be treated by oral administration instead of insulin injection, particularly for patients with type 1 diabetes. Means to solve
  • the present inventors easily form a metal complex between poly-gamma-glutamic acid generally used in foods and a metal source, and the complex is a sugar. It was confirmed that the therapeutic effect of urine disease was exhibited, and the present invention was completed.
  • the present invention comprises an anionic polyamino acid, preferably a metal-polyamino acid complex that can be produced from polygamma glutamic acid and a metal compound, preferably a metal-poly-gamma glutamic acid complex. It relates to a pharmaceutical composition for the treatment and prevention of diabetes. More particularly, the present invention relates to a metal-on-amino acid complex, preferably a metal-polygamma glutamic acid complex, preferably a metal-polygamma glutamic acid complex, and a pharmaceutically acceptable product. The present invention relates to a pharmaceutical composition for prevention of diabetes.
  • the present invention also relates to the treatment of diabetes with a metal-polyamino acid complex, preferably a metal-poly-gammer glutamic acid complex, which can be produced from an ionic polyamino acid, preferably polygamma glutamic acid and a metal compound. It relates to the use as a preventive agent.
  • a metal-polyamino acid complex preferably a metal-poly-gammer glutamic acid complex
  • an ionic polyamino acid preferably polygamma glutamic acid and a metal compound. It relates to the use as a preventive agent.
  • the present invention provides a metal polyamino acid complex which can be produced from an effective amount of a cation polyamino acid, preferably polygamma glutamic acid and a metal compound, in diabetic patients or patients who are expected to develop diabetes. Relates to a method for treating or preventing diabetes comprising administering a metal polygamma glutamate complex.
  • the present invention provides a treatment for diabetes of a metal-polyamino acid complex, preferably a metal-poly-gamma glutamic acid complex, which can be produced from an ionic polyamino acid, preferably polygamma glutamic acid and a metal compound. It relates to the use for the manufacture of a prophylactic pharmaceutical composition.
  • the present invention relates to a novel metal complex of a cation polyamino acid, preferably poly-1-gamma-glutamic acid and vanadium.
  • the present invention also relates to a food composition
  • a metal-polyamino acid complex which can be produced from a ergonal polyamino acid, preferably a polygamma glutamic acid and a metal compound.
  • a pharmaceutical composition for the treatment / prevention of diabetes comprising a metal-polyamino acid complex that can be produced from a ergonal polyamino acid and a metal compound.
  • the metal-polyamino acid complex has a hypoglycemic action, a glucose tolerance improving action, a hypotensive action, And the pharmaceutical composition according to any one of the above (1) to (8), which has at least one action of improving insulin resistance.
  • a food composition comprising a metal-polyamino acid complex that can be produced from a ergonal polyamino acid and a metal compound.
  • the metal-polyamino acid complex is a functional food having at least one of a hypoglycemic action, a glucose tolerance improving action, a blood pressure lowering action, and an insulin resistance improving action (13) to (19 ) Any one of the food compositions.
  • the terion polyamino acid in the present invention is a polymer of a natural or non-natural amino acid and has a eron functional group such as a carboxylic acid group or a sulfonic acid group. It is a polymer of mino acid, and a polymer such as glycine-yaalanin, which is chemically modified with a carboxyalkylamino group or a sulfoalkylamino group and having a carboxylic acid group or a sulfonic acid group, may be used.
  • preferred examples of the cation polyamino acid include polymers of acidic amino acids such as polyglutamic acid and polyaspartic acid. Such acidic amino acid polymers may be those polymerized at the ⁇ -position, but preferably include polygamma glutamic acid polymerized at the ⁇ -position, polyaspartic acid polymerized at the j8-position, and the like.
  • the amino acid in the cation polyamino acid of the present invention may be an optically active form such as D-form or L-form, or a racemate such as DL-form, or any mixture of D-form and L-form. It may be. Further, the amino acid in the cation polyamino acid of the present invention is not necessarily a polymer having a single amino acid force, but may be a polymer having two or more amino acid forces. Further, the cation polyamino acid of the present invention may be a derivative in which at least a part of the polymer is chemically modified.
  • the molecular weight (eg, weight average molecular weight) of the cation polyamino acid of the present invention is not particularly limited, but is preferably 5000 daltons or more, more preferably 10 kD to: LOOk D, and further preferably 10 kD. -80 kD is mentioned.
  • the cation polyamino acid of the present invention may be a natural one or a synthesized one. If there is a commercial product, it may be a commercial product.
  • a preferred cation polyamino acid of the present invention includes, for example, poly 1 gamma 1 dartamic acid.
  • the poly-1-gamma-glutamic acid may be any of poly ( ⁇ -L-dalamic acid), poly (0-D-glutamic acid), or poly ( ⁇ DL-glutamic acid). It may be a mixture of
  • a part of the glutamic acid may be substituted with another amino acid such as aspartic acid.
  • the content of glutamic acid in the poly-1-gamma-glutamic acid of the present invention is such that at least 50% or more of the amino acid residues of the polymer are contained as glutamic acid, preferably 80% or more, more preferably about 100%. It is a glutamic acid.
  • the molecular weight (eg, weight average molecular weight) of the polygamma glutamic acid of the present invention is not particularly limited, but is preferably 5000 daltons or more, more preferably 1 It is 0kD to 5000kD, and it is more preferable. ⁇ or 100kD to 3000kD.
  • the polygamma glutamic acid of the present invention may be produced using a polygamma glutamine-producing bacterium such as Bacillus natto, or a commercially available product that is a synthesized product may be used.
  • the poly gamma glutamic acid in the present invention may be a derivative of poly gamma glutamic acid, at least a part of which is chemically modified, and as a derivative thereof, natural poly gamma glutamic acid is combined with a metal.
  • Examples include those that have been chemically modified by various methods that do not adversely affect the formation of the body, such as those that have been alkylated or those that have introduced a sulfoalkylamino group (see JP 2002-80593), etc. Can be mentioned.
  • the metal compound used in the production of the metal polyamino acid complex includes a metal species containing a metal species as a metal source suitable for administration to humans and Z or other animals.
  • the compound is not particularly limited as long as it is a compound, but preferably a metal compound containing one or more metals selected from the group strength of vanadium, zinc, manganese, iron, cobalt, copper, tungsten, and chrome power. Can be mentioned.
  • a metal compound containing one or more metals selected from the group strength of vanadium, zinc, manganese, iron, cobalt, copper, tungsten, and chrome power Can be mentioned.
  • There is no particular limitation on the valence of these metals but a valence in a relatively oxidized state is preferable.
  • more preferable metal species include one or more metals selected from the group consist
  • the metal compound containing such a metal species may be a single metal!
  • Preferred examples include /, but mineral salts such as halides, hydroxides, sulfates and nitrates, and metal organic complexes.
  • organic acid salts, such as acetate, may be sufficient.
  • the method for producing a metal polyamino acid complex of the present invention can be produced by mixing the above-described polyionic amino acid and a metal compound in a solvent such as water. From the reaction mixture, the target metal polyamino acid complex can be purified and isolated by various known methods. When water is used as a solvent, the reaction mixture can be used as an aqueous solution with the target metal polyamino acid complex as it is or after concentration if necessary.
  • the metal polyamino acid complex of the present invention can be stably present together with the metal compound power containing the metal atom or metal species of the metal compound and the anionic polyamino acid, the metal species and the anionic polyamino acid are: It may be in a physically bonded state or in a chemically bonded state. Therefore, the metal-polyamino acid complex of the present invention may be a mixture in which a cation polyamino acid and a metal compound are physically uniformly bonded by physical adsorption or the like!
  • -It may be a metal salt of an ionic functional group of an ionic polyamino acid, or may be a complex such as a chelate of a metal species and a cation polyamino acid, and a metal atom or metal species It may be in a state of inclusion of a metal compound or the like contained! /.
  • the metal-polyamino acid complex of the present invention includes a polyamino acid complex containing a metal species as a metal source suitable for administration to humans and Z or other animals as described above, preferably vanadium.
  • a metal species as a metal source suitable for administration to humans and Z or other animals as described above, preferably vanadium.
  • the preferred polyamino acid in the metal polyamino acid complex of the present invention includes the aforementioned polyaspartic acid and polyglutamic acid, and more preferably polygamma glutamic acid.
  • Preferred examples of the metal polyamino acid complex of the present invention include a vanadium-polyaspartic acid complex, a vanadium-polyglutamic acid complex, a vanadium-poly-gamma-glutamic acid complex, a zinc-polyaspartic acid complex, Examples include zinc-polyglutamic acid complex, zinc-poly-gamma-glutamic acid complex, manganese-polyaspartic acid complex, manganese polyglutamic acid complex, and manganese polygamma glutamic acid complex.
  • More preferable metal polyamino acid complexes include, for example, vanadium-polyaspartic acid complex, nonadium-polyglutamic acid complex, vanadium polygamma glutamic acid complex, and among these, vanadium polygamma glutamic acid complex is used. More preferred is a metal polyamino acid complex.
  • vanadium-polyaspartic acid complex vanadium-polyaspartic acid complex
  • nonadium-polyglutamic acid complex vanadium polygamma glutamic acid complex
  • vanadium polygamma glutamic acid complex is used.
  • More preferred is a metal polyamino acid complex.
  • the present invention provides a novel vanadium-polyamino acid complex.
  • the vanadium polyamino acid complex of the present invention is considered to be one in which vanadium and polyamino acid form a complex like chelate.
  • Preferred vanadium polyamino acid complexes of the present invention include vanadium polygamma glutamic acid complexes.
  • the metal-polyamino acid complex of the present invention has an insulin-like action, as will be apparent from test examples described later, and can be used as a preventive or therapeutic agent for diabetes or hypertension.
  • the metal-polyamino acid complex of the present invention includes impaired glucose tolerance, diabetes (such as type 2 diabetes), insulin resistance syndrome (such as insulin receptor abnormality), polycystic ovary syndrome, hyperlipidemia, Atherosclerosis, cardiovascular disease (angina, heart failure, etc.), hyperglycemia, or hypertension, or angina, hypertension, pulmonary hypertension, congestive heart failure, diabetic complications (eg diabetic necrosis, diabetes It is useful as a medicine used as a prophylactic / therapeutic agent for osteoarthritis, diabetic glomerulosclerosis, diabetic skin disorder, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like. Accordingly, the present invention provides a pharmaceutical composition comprising the above-described metal polyamino acid complex of the present invention and a
  • the metal polyamino acid complex of the present invention is used as an active ingredient, such as an organic or inorganic solid or liquid excipient suitable for oral administration, parenteral administration or topical administration. It can be used in the form of a pharmaceutical preparation contained together with a pharmaceutically acceptable carrier.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalants, suppositories, solutions, mouth lotions, suspensions, emulsions, ointments, gels and the like. If necessary, the formulation may contain adjuvants, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives.
  • pH adjusters include basic aqueous solutions such as potassium hydroxide, sodium hydroxide, lithium hydroxide, and barium hydroxide, citrate buffer, and phosphate buffer. It is preferable to use a buffer solution such as liquid.
  • the therapeutically effective dose of the metal-polyamino acid complex of the present invention varies depending on the age and symptoms of the patient, but the average single dose of the metal-polyamino acid complex of the present invention is about 0.1 mgZ per person.
  • a dose of about 1 to 10 mg / day can be administered once or several times per day.
  • the food composition of the present invention is a food composition useful as a functional food or a health food for people who are concerned about blood sugar levels or who are concerned about health.
  • Examples of the food composition of the present invention include those containing the metal-polyamino acid complex of the present invention and a food carrier.
  • the food composition of the present invention can be made into a composition comprising the metal polyamino acid complex of the present invention together with a food carrier.
  • the metal polyamino acid complex of the present invention can be applied to other known foods.
  • the food composition of the present invention can also be blended with the body. That is, the food composition of the present invention can be provided as a simple substance, or can be provided as a food additive to other foods.
  • the form of the food composition of the present invention may be, for example, a powder, granule, tablet, or liquid.
  • the food composition of the present invention may further optionally contain excipients, disintegrants, binders, stabilizers, surfactants, dispersants, preservatives, buffers, emulsifiers, and the like as necessary. You can also.
  • the food composition of the present invention can be ingested in an amount of 1 to 50 g, preferably about 1 to 20 g per day, depending on the situation of the person who ingests, and particularly when the food composition of the present invention is ingested. There is no limit, but it can be taken before meals or with meals.
  • Diabetes is in a state of chronic energy deficiency, and fatty acids are released from the fat cells into the blood to make up for it, so the level of free fatty acid (FFA) in the blood rises.
  • FFA free fatty acid
  • the effect of inhibiting fatty acid release from adipocytes by the metal polyamino acid complex of the present invention can be used as an evaluation system for insulin-like action.
  • the insulin-like action of the metal polyamino acid complex of the present invention was evaluated as follows. As test compounds, the poly —Gamma monoglutamate Z vanadium complex ((VO) (PGA)) was used.
  • Vanadium oxosulfate (VOSO) was used as a positive control.
  • VOS0 vanadium oxosulfate
  • the polyamino acid complex of the present invention has an extremely excellent suppression effect as compared with conventional metal compounds.
  • Zn (PGA) polygamma glutamic acid Z zinc complex
  • ZnSO m n zinc sulfate
  • the polyamino acid complex of the present invention has an extremely excellent suppression effect as compared with conventional metal compounds.
  • an in vivo test was carried out using a mouse (STZ mouse) in which splenocyte ⁇ cells, which are insulin-secreting cells, were specifically destroyed by administration of streptozotocin (STZ) and made diabetic. Went.
  • the test compound was poly gamma glutamic acid ⁇ vanadium complex ((VO) (PGA)) as vanadium at a rate of 10mg / kg body weight.
  • FIG. 1 shows changes in blood glucose levels.
  • the vertical axis in Fig. 1 represents blood glucose level (mgZdL), and the horizontal axis represents time (hour).
  • the white triangle mark ( ⁇ ) in Fig. 1 shows the case where the (VO) (PGA) complex of the present invention is administered, and the black square mark (country) is a known V
  • black circle ( ⁇ ) is 2% polygamma glutamine for comparison
  • the anti-diabetic effect of the metal polyamino acid complex of the present invention after long-term administration was evaluated by measuring blood glucose level as needed using STZ mice of type 1 diabetes model animals. In other words, blood glucose levels were measured every day at 10 am, and poly-gamma-glutamate Z vanadium complex ((VO) (PGA)) was used as a test compound once a day for 17 days.
  • VO poly-gamma-glutamate Z vanadium complex
  • FIG. 2 shows the changes in blood glucose levels over the 17 days.
  • the vertical axis in Fig. 2 represents blood glucose level (mgZdL), and the horizontal axis represents the number of days (days).
  • the white square (mouth) in Fig. 2 is administered with the (VO) (PGA) complex of the present invention.
  • the black square mark (country) indicates the case where a known VOSO was administered, and the black circle mark ( ⁇ )
  • the m n complex was found to be about 5 times more effective. Furthermore, in the in vivo evaluation, as shown in FIGS. 1 and 2, the hypoglycemic effect of the (VO) (PGA) complex of the present invention is not dissolved.
  • the anti-diabetic action was evaluated by measuring blood glucose levels as needed using KK Ay mice, which are obese type 2 diabetes model animals. In other words, blood glucose levels were measured every day at 10 am, and Zn (PGA) complex was applied once a day for 30 days according to changes in blood glucose levels.
  • KK Ay mice which are obese type 2 diabetes model animals.
  • Zn (PGA) complex was applied once a day for 30 days according to changes in blood glucose levels.
  • Fig. 3 shows the blood glucose level for 30 days.
  • the vertical axis in FIG. 3 indicates blood glucose level (mgZdL), and the horizontal axis indicates the number of days (days).
  • the black triangle mark ( ⁇ ) in Fig. 3 shows the case where the ( Zn (PGA)) complex of the present invention was administered, and the white triangle
  • the symbol ( ⁇ ) indicates the case where a known ZnSO was administered, and the white circle symbol ( ⁇ ) represents a control.
  • KK— Ay mouse which is an obese diabetes model mouse, as a type 2 diabetes model animal. Changes in blood glucose levels once a day for 30 days using test compound Z-zinc (Zn (PGA)) complex
  • the metal polyamino acid complex of the present invention is extremely effective as compared with conventional metal compounds, and a complex composed of these two compounds by using a polyamino acid. Is considered to be a sustained-release agent. Therefore, it is estimated that vanadium, which exhibits anti-diabetic action, was continuously supplied to the body and exerted a strong effect.
  • the metal polyamino acid complex of the present invention is useful as a 'preventive agent for treating diabetes', particularly as a therapeutic' preventive agent for diabetes that can be administered orally.
  • the metal polyamino acid complex of the present invention particularly the metal polygamma glutamic acid complex according to the present invention has better stability as it is less toxic than metal ions, has a better fat solubility, and has a higher solubility. Hypoglycemic effect, glucose tolerance improving effect, blood pressure lowering effect, and It is highly expected as a therapeutic agent for diabetes having a phosphorus resistance improving action.
  • the metal polyamino acid complex of the present invention is extremely easy to manufacture, is safe without substantial side effects even during long-term ingestion, and is useful as a practical therapeutic / preventive drug. is there.
  • the metal polyamino acid complex of the present invention is highly safe and has a hypoglycemic action, a glucose tolerance improving action, a blood pressure lowering action, and an insulin resistance improving action, which can be further administered orally. It is also useful as a food composition containing, particularly a functional food composition, or a food additive comprising the same.
  • FIG. 1 is a graph showing a hypoglycemic effect when the poly-gamma glutamate Z vanadium complex of the present invention ((VO) (PGA)) is orally administered to give lOmg VZkg body weight. is there.
  • the graph in Fig. 1 shows (VO) (PGA) complex ( ⁇ mark) and VOSO as a comparison (country mark m n 4
  • FIG. 2 is a graph showing the hypoglycemic effect when the polygamma glutamate Z vanadium complex ((VO) (PGA)) of the present invention is orally administered once a day for 17 consecutive days.
  • the graph in Figure 2 shows the (VO) (PGA) complex (mouth seal), VOSO as a comparison (country mark), comparison and m n 4
  • FIG. 3 is a graph showing the hypoglycemic effect of the poly-gamma-monoglutamate Z-zinc (Zn (PGA)) complex of the present invention administered orally once daily for 30 days.
  • the graph in Figure 3 shows the Zn (PGA) complex (marked with ⁇ ), ZnSO as a comparison (marked with ⁇ ), and m n 4 as the control.
  • IR represents an infrared absorption spectrum
  • UVZ VIS represents a visible ultraviolet absorption spectrum
  • ESR represents an electron spin resonance spectrum
  • Example 2 In the same manner as in Example 1, 1% or 2% poly-gamma glutamic acid aqueous solution and 1M zinc sulfate aqueous solution manufactured by Bio-Riders Japan Co., Ltd. The mixture was stirred while adjusting pH appropriately with HC1. The obtained aqueous solution was made into a Zn (PGA) complex aqueous solution and used as a test substance.
  • PGA Zn
  • KRB buffer (10 mM glucose, 120 mM NaCl, 1.27 mM CaCl .75 mM KC1) containing 20 mg bovine serum albumin (BSA) and 0.4 mg collagenase per ml.
  • BSA bovine serum albumin
  • rat adipocytes The effect on rat adipocytes is that the adipocytes (1.5 X 10 6 cells / ml) isolated above in the silicon-treated dial were used at various concentrations (10 _4 , 5 X 10 " 4 , 10 _3 with Pojiti Bed control or test substance M), 37 ° C in KRB buffer one, and 0.5 hours Pureinkyu Pies, then the reaction mixture Epinefurin of 10 _5 M Ka ⁇ E, the resulting solution at 37 ° C After incubation for 3 hours, the reaction mixture was ice-cooled and centrifuged at 3000 rpm for 10 minutes.For the extracellular solution, free fatty acid (FFA) levels were measured using NEFA kit WAKO. IC values were measured.
  • FFA free fatty acid
  • the anti-diabetic action of the (VO) (PGA) complex of the present invention is the STZ mn of type 1 diabetes model animals.
  • the (VO) (PGA) complex should be added so that the amount of vanadium is 10 mg / kg body weight.
  • the anti-diabetic effect of long-term administration of the (VO) (PGA) complex of the present invention is expressed as type 1 diabetes m n
  • STZ mice were orally administered to a body weight of 3 mg to LOmg VZkg according to changes in blood glucose level.
  • Figure 2 shows the changes in blood glucose levels over the 17 days.
  • the antidiabetic effect of the administration was evaluated by measuring blood glucose levels as needed using KK Ay mice, which are obese type 2 diabetes model animals. In other words, blood glucose level is measured every day at 10 am and Zn (PGA) complex is
  • KK- Ay mice were orally administered to a body weight of 10-20 mgZnZkg according to changes in blood glucose level.
  • Figure 3 shows the results of changes in blood glucose levels over 30 days.
  • the present invention provides a novel antidiabetic drug and has industrial applicability in the pharmaceutical industry and the like.
  • the present invention provides food compositions such as food additives and supplements containing a metal-polyamino acid complex, and has industrial applicability in the food industry and the like.

Abstract

La présente invention concerne un agent de traitement du diabète, en particulier un agent de traitement du diabète pouvant être administré oralement en toute sécurité, même pendant une période prolongée. L'invention concerne une composition pharmaceutique destinée au traitement ou à la prévention du diabète comprenant un polyamino acide anionique, de préférence un complexe métal-polyamino acide qui peut être produit à partir d'acide poly-gamma-glutamique et d'un composé métallique. L'invention concerne plus particulièrement la composition pharmaceutique destinée au traitement ou à la prévention du diabète qui comprend un polyamino acide anionique, de préférence un complexe métal-polyamino acide qui peut être produit à partir d'acide poly-gamma-glutamique et d'un composé métallique, et qui possède au moins une des actions suivantes : action hypoglycémique, action d'amélioration de la tolérance au glucose, action de réduction de la pression sanguine et action d'amélioration de la résistance à l'insuline. En outre, L'invention concerne une composition alimentaire comprenant un polyamino acide anionique, de préférence un complexe métal-polyamino acide qui peut être produit à partir d'acide poly-gamma-glutamique et d'un composé métallique.
PCT/JP2006/320375 2005-10-12 2006-10-12 Agent antidiabétique comprenant un complexe métal-polyamino acide anionique WO2007043606A1 (fr)

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WO2010081862A2 (fr) * 2009-01-14 2010-07-22 Katholieke Universiteit Leuven, K.U. Leuven R&D Méthodes et préparations pour la protection de patients en état critique
JP2011037842A (ja) * 2009-07-16 2011-02-24 Kao Corp 血中ｇｉｐ濃度上昇抑制剤
JP2011037843A (ja) * 2009-07-16 2011-02-24 Kao Corp 食後血中インスリン濃度上昇抑制剤
JP2011084505A (ja) * 2009-10-15 2011-04-28 Kyowa Chem Ind Co Ltd 膵臓機能強化乃至活性化用無機化合物粒子
JP2011178764A (ja) * 2010-03-04 2011-09-15 Ajinomoto Co Inc 腸内ビフィズス菌増殖促進剤および腸管バリア機能改善剤
CN102302511A (zh) * 2010-06-24 2012-01-04 攀枝花兴辰钒钛有限公司 一种药物组合物在制备治疗器质性性功能障碍的药物中的用途
KR101200671B1 (ko) 2010-08-11 2012-11-12 한국식품연구원 폴리감마글루탐산을 유효성분으로 함유하는 비만예방 및 치료용 조성물
US9056066B2 (en) 2011-01-12 2015-06-16 Kao Corporation Agent for suppressing elevation of blood GIP level, agent for suppressing elevation of blood insulin level, agent for lowering blood triglyceride level after meal ingestion, and agent for suppressing elevation of blood glucose level
JP2017535580A (ja) * 2014-11-25 2017-11-30 普惠徳生技股▲ふん▼有限公司 糖尿病の改善に供する医薬品の製造のための第一鉄アミノ酸キレートを含む組成物の使用
EP2455088B1 (fr) * 2009-07-16 2018-03-07 Kao Corporation Inhibiteur de l élévation du taux de triglycérides dans le sang
WO2018084805A1 (fr) * 2016-11-01 2018-05-11 Xylonix Ip Holdings Pte. Ltd. Compositions d'acide gamma-polyglutamique et de zinc
KR20190120159A (ko) * 2016-11-01 2019-10-23 자일로닉스 아이피 홀딩스 피티이. 엘티디. 아연-γ-PGA 조성물 및 암을 치료하기 위한 방법
WO2020004712A1 (fr) * 2018-06-28 2020-01-02 배진호 Composition complexe d'acide polyglutamique, soluble dans l'eau, contenant du zinc
JP2021501143A (ja) * 2017-10-30 2021-01-14 ジロニックス・アイピー・ホールディングス・ピーティーイー．リミテッド がんを処置するためのアルファ−ポリグルタミン酸−亜鉛を含む組成物
CN117224690A (zh) * 2023-11-10 2023-12-15 江苏海王健康生物科技有限公司 一种作为助剂的γ-聚谷氨酸混合物、组合物、制备方法
JP7466822B2 (ja) 2016-11-01 2024-04-15 ジロニックス・ピーティーイー．リミテッド 亜鉛－γ－ＰＧＡ組成物およびがんを処置するための方法

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WO2010081862A3 (fr) * 2009-01-14 2010-10-07 Katholieke Universiteit Leuven, K.U. Leuven R&D Méthodes et préparations pour la protection de patients en état critique
WO2010081862A2 (fr) * 2009-01-14 2010-07-22 Katholieke Universiteit Leuven, K.U. Leuven R&D Méthodes et préparations pour la protection de patients en état critique
US8933025B2 (en) 2009-07-16 2015-01-13 Kao Corporation Agent for suppressing postprandial elevation of blood insulin concentration
JP2011037842A (ja) * 2009-07-16 2011-02-24 Kao Corp 血中ｇｉｐ濃度上昇抑制剤
JP2011037843A (ja) * 2009-07-16 2011-02-24 Kao Corp 食後血中インスリン濃度上昇抑制剤
EP2455088B1 (fr) * 2009-07-16 2018-03-07 Kao Corporation Inhibiteur de l élévation du taux de triglycérides dans le sang
EP2455090A1 (fr) * 2009-07-16 2012-05-23 Kao Corporation Agent pour l inhibition de l augmentation du taux d insuline postprandiale dans le sang
EP2455090A4 (fr) * 2009-07-16 2013-01-02 Kao Corp Agent pour l inhibition de l augmentation du taux d insuline postprandiale dans le sang
US8853153B2 (en) 2009-07-16 2014-10-07 Kao Corporation Agent for suppressing elevation of blood GIP concentration
JP2011084505A (ja) * 2009-10-15 2011-04-28 Kyowa Chem Ind Co Ltd 膵臓機能強化乃至活性化用無機化合物粒子
JP2011178764A (ja) * 2010-03-04 2011-09-15 Ajinomoto Co Inc 腸内ビフィズス菌増殖促進剤および腸管バリア機能改善剤
CN102302511B (zh) * 2010-06-24 2015-06-03 攀枝花兴辰钒钛有限公司 一种药物组合物在制备治疗器质性性功能障碍的药物中的用途
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US9056066B2 (en) 2011-01-12 2015-06-16 Kao Corporation Agent for suppressing elevation of blood GIP level, agent for suppressing elevation of blood insulin level, agent for lowering blood triglyceride level after meal ingestion, and agent for suppressing elevation of blood glucose level
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